Quality of life in patients with K-RAS wild-type colorectal cancer: the CO.20 phase 3 randomized trial.

BACKGROUND: The CO.20 trial randomized patients with K-RAS wild-type, chemotherapy-refractory, metastatic colorectal cancer to receive cetuximab (CET) plus brivanib alaninate (BRIV) or CET plus placebo (CET/placebo). METHODS: Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 at baseline and at 2, 4, 6, 8, 12, 16, and 24 weeks until disease progression. Predefined coprimary QoL endpoints were time to deterioration (first worsening from baseline of ≥ 10 points) on the Physical Function (PF) and Global (GHS) scales. RESULTS: Of 750 randomized patients, 721 (358 of whom received CET/BRIV) were assessable for QoL. QoL compliance and baseline PF and GHS scores did not differ by treatment arm. The median time to deterioration was 1.6 months versus 1.1 months for GHS (P =.02) and 5.6 months versus 1.7 months for PF (P <.0001) favoring CET/placebo. Secondary analysis favored CET/placebo for QOL response on the PF, Cognitive Function, Fatigue, Nausea, Appetite, and Diarrhea scales. A greater percentage of patients on the CET/BRIV arm had PF worsening at 6 weeks (31% vs 17%). Clinical adverse events of ≥ grade 3 were more common with CET/BRIV than with CET/placebo, including fatigue (25% vs 11%), hypertension, rash, diarrhea, abdominal pain, dehydration, and anorexia. CONCLUSIONS: Compared with CET/placebo, the combination of CET/BRIV worsened time to QoL deterioration for patients with K-RAS wild-type, chemotherapy-refractory, metastatic colorectal cancer on the PF and GHS scales of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. This result may be due to higher rates of fatigue and gastrointestinal adverse events.

Health-related quality of life with adjuvant docetaxel- and trastuzumab-based regimens in patients with node-positive and high-risk node-negative, HER2-positive early breast cancer: results from the BCIRG 006 Study.

BACKGROUND: This study aims to describe and compare health-related quality of life (HRQL) in patients with node-positive and high-risk node-negative HER2-positive early breast cancer receiving adjuvant docetaxel and trastuzumab-based or docetaxel-based regimens alone. METHODS: Eligible patients (n = 3,222) were randomly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC→T) or one of two trastuzumab-containing regimens: adjuvant doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab administered for 1 year (AC→TH) or six cycles of docetaxel plus carboplatin combined with trastuzumab administered for 1 year (TCH). The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and BR-23 were administered at baseline, the start of cycle 4 (mid), and the end of chemotherapy (EOC), as well as at 6, 12, and 24 months after chemotherapy. RESULTS: Compliance rates for the EORTC questionnaires were acceptable at 72%-93% of eligible patients out to the 12-month assessment. Systemic side effect (SE) change scores were significantly improved for TCH-treated patients compared with AC→TH and AC→T at EOC, suggesting improved tolerability. Physical functioning (PF) was only slightly worse at midpoint for those receiving TCH, compared with patients who were just starting on taxane in an AC→TH regimen, but was otherwise similar between arms. All treatment arms recovered from the deterioration in SE, PF, and Global Health Scale scores by 1 year and median future perspective change scores continued to improve throughout treatment and follow-up. CONCLUSION: HRQL outcomes for adjuvant docetaxel and trastuzumab-based regimens are favorable and support TCH as a more tolerable treatment option.

Guidelines for health technologies: specific guidance for oncology products in Canada.

OBJECTIVE: Specific methodological challenges are often encountered during cancer-related economic evaluations. The objective of this study was to provide specific guidance to analysts on the methods for the conduct of high-quality economic evaluations in oncology by building on the Canadian Agency for Drugs and Technologies in Health Guidelines for the Economic Evaluation of Health Technologies (third edition). METHODS: Fifteen oncologists, health economists, health services researchers, and decision makers from across Canada identified sections in Canadian Agency for Drugs and Technologies in Health guidelines that would benefit from oncology-specific guidance. Fifteen sections of the guidelines were reviewed to determine whether 1) Canadian Agency for Drugs and Technologies in Health guidelines were sufficient for the conduct of oncology economic evaluations without further guidance specific for oncology products or 2) additional guidance was necessary. A scoping review was conducted by using a comprehensive and replicable search to identify relevant literature to inform recommendations. Recommendations were reviewed by representatives of academia, government, and the pharmaceutical industry in an iterative and formal review of the recommendations. RESULTS: Major adaptations for guidance related to time horizon, effectiveness, modeling, costs, and resources were required. Recommendations around the use of final outcomes over intermediate outcomes to calculate quality-adjusted life-years and life-years gained, the type of evidence, the source of evidence, and the use of time horizon and modeling were made. CONCLUSIONS: This article summarizes key recommendations for the conduct of economic evaluations in oncology and describes methods required to ensure that economic assessments in oncology are conducted in a standardized manner.

Factors associated with delays to medical assessment and diagnosis for patients with colorectal cancer.

OBJECTIVE: To identify factors associated with delays to medical assessment and diagnosis for patients with colorectal cancer (CRC). DESIGN: Data were collected through a standardized questionnaire. Clinical records were also reviewed. When necessary, patients were contacted by a member of the study team to collect missing data and confirm information. SETTING: Cross Cancer Institute in Edmonton, Alta. PARTICIPANTS: Patients newly diagnosed with a histologically proven colorectal adenocarcinoma were identified and eligible for the study. MAIN OUTCOME MEASURES: Associations between symptoms, tumour stage at operation, symptom duration, and tumour location were sought to identify factors associated with a delay in diagnosis of CRC. RESULTS: Surveys were completed by 93 patients. A total of 49% of patients had symptoms of CRC present for 1 month or less before seeing a physician, and 51% had symptoms for longer than 1 month. Seventy-five (86%) patients initially presented to family physicians for assessment, while 12 (14%) patients presented to the emergency department for their first physician encounters. Only 33 (38%) patients had digital rectal examinations during their first visits. Women were more likely to present to physicians with longer than 1 month of symptoms, while men were more likely to present with less than 1 month of symptoms (P = .03). Abdominal pain, blood in the stool, and change in stool size were the most frequent symptoms encountered. Twenty-two (26%) patients delayed seeking treatment because they thought their symptoms were not serious and 12 (14%) believed that their family physicians had taken inappropriate action. Fifteen (18%) patients attributed their delays to waiting too long for specialist referral and diagnostic tests. CONCLUSION: This study highlights the important role patients and physicians both play in delays in the diagnosis of CRC. Efforts to diminish future delays must focus on educating the public and practising physicians about important symptoms and signs of CRC. Additionally, the value of a digital rectal examination must be emphasized, along with continued promotion of CRC screening.

K-ras mutations and benefit from cetuximab in advanced colorectal cancer.

BACKGROUND: Treatment with cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, improves overall and progression-free survival and preserves the quality of life in patients with colorectal cancer that has not responded to chemotherapy. The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value. METHODS: We analyzed tumor samples, obtained from 394 of 572 patients (68.9%) with colorectal cancer who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone, to look for activating mutations in exon 2 of the K-ras gene. We assessed whether the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups. RESULTS: Of the tumors evaluated for K-ras mutations, 42.3% had at least one mutation in exon 2 of the gene. The effectiveness of cetuximab was significantly associated with K-ras mutation status (P=0.01 and P<0.001 for the interaction of K-ras mutation status with overall survival and progression-free survival, respectively). In patients with wild-type K-ras tumors, treatment with cetuximab as compared with supportive care alone significantly improved overall survival (median, 9.5 vs. 4.8 months; hazard ratio for death, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001) and progression-free survival (median, 3.7 months vs. 1.9 months; hazard ratio for progression or death, 0.40; 95% CI, 0.30 to 0.54; P<0.001). Among patients with mutated K-ras tumors, there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to overall survival (hazard ratio, 0.98; P=0.89) or progression-free survival (hazard ratio, 0.99; P=0.96). In the group of patients receiving best supportive care alone, the mutation status of the K-ras gene was not significantly associated with overall survival (hazard ratio for death, 1.01; P=0.97). CONCLUSIONS: Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab. The mutation status of the K-ras gene had no influence on survival among patients treated with best supportive care alone. (ClinicalTrials.gov number, NCT00079066.)

Cetuximab for the treatment of colorectal cancer.

BACKGROUND: Cetuximab, an IgG1 chimeric monoclonal antibody against epidermal growth factor receptor (EGFR), has activity against colorectal cancers that express EGFR. METHODS: From December 2003 to August 2005, 572 patients who had colorectal cancer expressing immunohistochemically detectable EGFR and who had been previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin or had contraindications to treatment with these drugs underwent randomization to an initial dose of 400 mg of cetuximab per square meter of body-surface area followed by a weekly infusion of 250 mg per square meter plus best supportive care (287 patients) or best supportive care alone (285 patients). The primary end point was overall survival. RESULTS: In comparison with best supportive care alone, cetuximab treatment was associated with a significant improvement in overall survival (hazard ratio for death, 0.77; 95% confidence interval [CI], 0.64 to 0.92; P=0.005) and in progression-free survival (hazard ratio for disease progression or death, 0.68; 95% CI, 0.57 to 0.80; P<0.001). These benefits were robust after adjustment in a multivariable Cox proportional-hazards model. The median overall survival was 6.1 months in the cetuximab group and 4.6 months in the group assigned to supportive care alone. Partial responses occurred in 23 patients (8.0%) in the cetuximab group but in none in the group assigned to supportive care alone (P<0.001); the disease was stable in an additional 31.4% of patients assigned to cetuximab and in 10.9% of patients assigned to supportive care alone (P<0.001). Quality of life was better preserved in the cetuximab group, with less deterioration in physical function and global health status scores (both P<0.05). Cetuximab treatment was associated with a characteristic rash; a rash of grade 2 or higher was strongly associated with improved survival (hazard ratio for death, 0.33; 95% CI, 0.22 to 0.50; P<0.001). The incidence of any adverse event of grade 3 or higher was 78.5% in the cetuximab group and 59.1% in the group assigned to supportive care alone (P<0.001). CONCLUSIONS: Cetuximab improves overall survival and progression-free survival and preserves quality-of-life measures in patients with colorectal cancer in whom other treatments have failed. (ClinicalTrials.gov number, NCT00079066 [ClinicalTrials.gov].).

Cost-effectiveness analysis of adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) for node-positive breast cancer: modeling the downstream effects.

PURPOSE: BCIRG 001 demonstrated prolonged disease-free (DFS) and overall survival (OS) but increased toxicity for adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) versus 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) in women with node positive breast cancer (BC). This study evaluates quality-adjusted survival and cost-effectiveness of adjuvant TAC versus FAC, taking downstream decisions and events into account, including palliative chemotherapy with taxanes. METHODS: We developed a Markov model for a cohort of women with node positive BC eligible for adjuvant anthracyclines. Data input included clinical and resource utilization data collected prospectively from BCIRG 001. Treatment decisions and outcomes with disease recurrence were based on a systematic literature review with validity reviewed by a national panel of Canadian BC oncologists. Direct costs for resource utilization following Canadian practice patterns were included. Unit costs were obtained from provincial cost list and published drug list prices. Utility scores were derived from the literature. An incremental cost-effectiveness ratio (ICER) in cost per quality-adjusted life-years (QALY) gained for TAC versus FAC was calculated. RESULTS: For 1,000 women with node positive BC, the model showed that TAC would lead to a gain of 313 QALY (370 life years) at an additional cost of $5.8 Million Canadian dollars (Cdn) compared to FAC, over a 10-year time horizon. The ICER of TAC versus FAC was $18,505.54 Cdn per QALY gained. Sensitivity analyses supported the robustness of the model. By one-way sensitivity analyses of over 50 model variables, 95% of the cumulative ICER variation was from $6,000 to $28,000 Cdn/QALY. By multivariate Monte Carlo simulation, there was a 70% probability that the ICER would be under $50,000 CdN/QALY. CONCLUSION: For women with node positive BC, TAC improves DFS and OS compared to FAC and is a cost-effective adjuvant chemotherapy strategy.

Community compliance with carcinoembryonic antigen: follow-up of patients with colorectal cancer.

PURPOSE: The aim of this study was to determine whether recommendations for surveillance carcinoembryonic antigen (CEA) testing in stage II/III colorectal cancer (CRC) are adhered to upon discharge from our cancer center, patterns of care after CEA elevation, and whether differences in outcomes exist between patients who did and did not receive recommended CEA monitoring. PATIENTS AND METHODS: A retrospective, single-institution chart review was completed at the Cross Cancer Institute (CCI) in Edmonton, Alberta. The Alberta Cancer Registry (ACR) identified patients with CRC diagnosed between January 1 and December 31, 2001. Patients with stage II/III CRC seen and/or treated at the CCI and later discharged to the community with follow-up recommendations based on American Society of Clinical Oncology guidelines were included. Carcinoembryonic antigen monitoring > or = every 4 months for > or = 2 years was deemed acceptable for study purposes. RESULTS: The ACR identified 152 stage II/III CRC cases meeting inclusion criteria. Eleven patients (7.2%) received the minimum predefined CEA follow-up. Eighty-seven CEA follow-up tests were elevated; only 20 (23%) elevated CEAs were investigated with predefined timely intervention. Twenty-six patients (17.1%) had documentable tumor recurrence. There was no difference in overall survival or time to recurrence between the groups who received and did not receive appropriate follow-up, although small numbers limit the effectiveness of statistical analysis. CONCLUSION: Post-therapy surveillance is important in CRC management. Our study reveals follow-up recommendations based on best available evidence for interval CEA testing are not followed in the community. These findings suggest the need for review of recommendations and change in management for monitoring discharged patients with stage II/III CRC.

Associations between exercise, quality of life, and fatigue in colorectal cancer survivors.

PURPOSE: This study was designed to examine quality of life and fatigue in colorectal cancer survivors meeting and not meeting public health exercise guidelines. METHODS: A Canadian provincial cancer registry identified colorectal cancer survivors who were mailed a questionnaire that assessed self-reported exercise, quality of life (Functional Assessment of Cancer Therapy - Colorectal), fatigue, medical, and demographic variables. RESULTS: Completed questionnaires were received from 413 (61.3 percent) eligible colorectal cancer survivors. Only 25.9 percent of colorectal cancer survivors reported meeting exercise guidelines. Colorectal cancer survivors meeting public health exercise guidelines reported clinically and significantly better quality of life (mean difference, 6; 95 percent confidence interval, 2.3-9.8; P = 0.002) and fatigue (mean difference = 5.2; 95 percent confidence interval, 2.9-7.5; P < 0.001). Differences remained after adjusting for medical and demographic factors. Cancer site (i.e., colon vs. rectal) was the only variable to moderate this association (P < 0.05 for interaction). CONCLUSIONS: Colorectal cancer survivors meeting public health exercise guidelines reported significantly and meaningfully better quality of life and fatigue scores than colorectal cancer survivors who did not meet guidelines. Prospective observational studies and randomized, controlled trials are needed to further assess the causal nature of these relationships.

Palliative chemoradiotherapy versus radiotherapy alone for dysphagia in advanced oesophageal cancer: a multicentre randomised controlled trial (TROG 03.01).

BACKGROUND: A short course of radiotherapy is commonly prescribed for palliative relief of malignant dysphagia in patients with incurable oesophageal cancer. We compared chemoradiotherapy with radiotherapy alone for dysphagia relief in the palliative setting. METHODS: This multicentre randomised controlled trial included patients with advanced or metastatic oesophageal cancer who were randomly assigned (1:1) through a computer-generated adaptive biased coin design to either palliative chemoradiotherapy or radiotherapy alone for treatment of malignant dysphagia at 22 hospitals in Australia, Canada, New Zealand, and the UK. Eligible patients had biopsy-proven oesophageal cancer that was unsuitable for curative treatment, symptomatic dysphagia, Eastern Cooperative Oncology Group performance status 0-2, and adequate haematological and renal function. Patients were stratified by hospital, dysphagia score (Mellow scale 1-4), and presence of metastases. The radiotherapy dose was 35 Gy in 15 fractions over 3 weeks for patients in Australia and New Zealand and 30 Gy in ten fractions over 2 weeks for patients in Canada and the UK. Chemotherapy consisted of one cycle of intravenous cisplatin (either 80 mg/m2 on day 1 or 20 mg/m2 per day on days 1-4 of radiotherapy at clinician's discretion) and intravenous fluorouracil 800 mg/m2 per day on days 1-4 of radiotherapy in week 1. Patients were assessed weekly during treatment. The primary endpoint was dysphagia relief (defined as ≥1 point reduction on the Mellow scale at 9 weeks and maintained 4 weeks later), and key secondary endpoints were dysphagia progression-free survival (defined as a worsening of at least 1 point on the Mellow scale from baseline or best response) and overall survival. These endpoints were analysed in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00193882. This trial is closed. FINDINGS: Between July 7, 2003, and March 21, 2012, 111 patients were randomly assigned to chemoradiotherapy and 109 patients to radiotherapy. One patient in the chemoradiotherapy group was omitted from analysis because of ineligibility. 50 (45%, 95% CI 36-55) patients in the chemoradiotherapy group and 38 (35%, 26-44) in the radiotherapy group obtained dysphagia relief (difference 10·6%, 95% CI -2 to 23; p=0·13). Median dysphagia progression-free survival was 4·1 months (95% CI 3·5-4·8) versus 3·4 months (3·1-4·3) in the chemoradiotherapy and radiotherapy groups, respectively (p=0·58), and median overall survival was 6·9 months (95% CI 5·1-8·3) versus 6·7 months (4·9-8·0), respectively (p=0·88). Of the 211 patients who commenced radiotherapy, grade 3-4 acute toxicity occurred in 38 (36%) patients in the chemoradiotherapy group and in 17 (16%) patients in the radiotherapy group (p=0·0017). Anaemia, thrombocytopenia, neutropenia, oesophagitis, diarrhoea, nausea and vomiting, and mucositis were significantly worse in patients who had chemoradiotherapy than in patients who had radiotherapy. INTERPRETATION: Palliative chemoradiotherapy showed a modest, but not statistically significant, increase in dysphagia relief compared with radiotherapy alone, with minimal improvement in dysphagia progression-free survival and overall survival with chemoradiotherapy but at a cost of increased toxicity. A short course of radiotherapy alone should be considered a safe and well tolerated treatment for malignant dysphagia in the palliative setting. FUNDING: National Health and Medical Research Council, Canadian Cancer Society Research Institute, Canadian Cancer Trials Group, Trans Tasman Radiation Oncology Group, and Cancer Australia.

A Uridine Glucuronosyltransferase 2B7 Polymorphism Predicts Epirubicin Clearance and Outcomes in Early-Stage Breast Cancer.

BACKGROUND: Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7), an enzyme rich in single nucleotide polymorphisms (SNPs). We studied whether the -161 C > T germline SNP in UGT2B7 was related to epirubicin metabolism and whether differences exist in the toxicity and efficacy of epirubicin-based chemotherapy among patients who were TT homozygotes, CT heterozygotes, and CC homozygotes. PATIENTS AND METHODS: A total of 132 women with non-metastatic breast cancer receiving FEC (5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), cyclophosphamide 500 mg/m(2)) were prospectively enrolled. Toxicity was assessed in cycle 1 using the National Cancer Institute Common Toxicity Criteria, version 2.0. RESULTS: The sequence at -161 was studied in 132 subjects; 37 were TT homozygotes, 63 were CT heterozygotes, 26 were CC homozygotes, and 6 could not be genotyped. The CC genotype patients had decreased epirubicin clearance (median, 103.3 L/hr) compared with the CT/TT genotype patients (median, 134.0 L/hr; P = .002). The CC homozygous patients had an increased risk of grade 3 to 4 leukopenia compared with the TT homozygotes or heterozygotes (P = .038 and P = .032, respectively). TT homozygotes or heterozygotes had an increased risk of early recurrence (P = .039; χ(2) test). CONCLUSION: The results of the present prospective pharmacogenetic study suggest that the UGT2B7 -161 C > T SNP correlate with drug metabolism, toxicity, and efficacy in patients receiving epirubicin chemotherapy. Further studies of this UGT2B7 SNP as a predictor of epirubicin toxicity and efficacy are warranted.

A randomized, phase III, double-blind, placebo-controlled trial of intrapleural instillation of methylprednisolone acetate in the management of malignant pleural effusion.

STUDY OBJECTIVES: To determine if intrapleural administration of methylprednisolone acetate (MA) after therapeutic thoracentesis for symptomatic malignant pleural effusion improved time to repeat thoracentesis for symptom control, quality of life (QOL), and dyspnea. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: A tertiary care cancer treatment center in Edmonton, AB, Canada. PATIENT SELECTION: Patients with symptomatic pleural effusions secondary to disseminated malignancy requiring therapeutic thoracentesis for symptom control. INTERVENTIONS: Sixty-seven patients underwent ultrasound-guided therapeutic thoracentesis for management of symptomatic malignant pleural effusion. Patients were randomly and blindly assigned to either 160 mg (8 mL) of MA or 8 mL of saline solution instilled into the pleural space. Patients were followed up for 6 weeks to determine the time to repeat therapeutic thoracentesis. All patients completed the Functional Assessment of Cancer Therapy-General (FACT-G) QOL questionnaire and a dyspnea visual analog scale (VAS) at baseline and again 2 weeks later. MEASUREMENTS AND RESULTS: Thirty-three patients received MA, and 34 patients received placebo; baseline characteristics for the two groups were similar, apart from a slightly higher use of concurrent systemic therapy in the placebo group. At 6 weeks follow-up, 50% of MA-treated patients required repeat thoracentesis compared to 56% of placebo-treated patients (not significant [NS]). The mean of the individual FACT-G change scores (2 weeks - baseline) was similar in the two groups (NS). VAS scores improved for both groups over the 2-week period, but the mean change scores (2 weeks - baseline) were not statistically different. CONCLUSION: Despite previous case series describing benefit from intrapleural MA in malignant pleural effusion, this controlled study of intrapleural MA instillation did not delay reaccumulation of symptomatic pleural effusion compared to placebo, nor were differences in QOL or dyspnea observed.

Final results of a phase II clinical trial of weekly docetaxel in combination with capecitabine in anthracycline-pretreated metastatic breast cancer.

The addition of capecitabine to docetaxel on a 3-week schedule resulted in superior response rate, increased time to progression (TTP), and improved overall survival in patients with anthracycline-pretreated metastatic breast cancer (MBC). Because the toxicity profile of weekly docetaxel differs from the standard 21-day docetaxel schedule, we performed a phase I/II trial to test the efficacy and safety of weekly docetaxel in combination with capecitabine given for 14 days every 21 days. The phase I study identified the doses of docetaxel (30 mg/m2 weekly) and capecitabine (900 mg/m2 twice daily on days 1-14 every 21 days) used in phase II. Twenty female patients with measurable or assessable MBC were enrolled. Eighteen patients had previously received anthracyclines; 2 had contraindications to anthracyclines. Patients remained on study for a maximum of eight 3-week cycles or until tumor progression or unacceptable toxicity occurred; response assessments were scheduled after cycle 2, 5, and 8. Seventeen patients were assessed after cycle 2; 3 subjects (18%) had a partial response (PR), 9 had stable disease (53%; SD), and 5 patients (29%) had progressive disease (PD). Ten patients were assessable after cycle 5. Two patients (20%) had a PR, 5 patients (50%) had SD, and 3 patients (30%) had PD. The most common grade 3 toxicities were nail loss (45%), asthenia (30%), and hand-foot syndrome (30%), and toxicities led to study discontinuation in 10 patients. The median time to treatment failure was 10 weeks and median TTP was 26 weeks. The median duration of response was 9 weeks and the median duration of SD was 16 weeks. The median overall survival was 82 weeks. This schedule of weekly docetaxel in combination with day 1-14 capecitabine has activity; however, toxicity discourages the use of this schedule in lieu of the standard docetaxel/capecitabine regimen.

Systematic review of management of colorectal cancer in elderly patients.

This study is designed to clarify the benefits and risks of chemotherapy and radiation therapy in elderly patients with colorectal cancer through a systematic review of the literature. Searches of the Medline, Embase, and Cochrane Library databases; PDQ Cancer Information Summaries, American Society of Clinical Oncology Guidelines, Cancer Care Ontario Practice Guideline Initiative, Interprovincial Drug Strategies and Guidelines Group, and OncoLink Web sites; and manual searches of meeting proceedings and bibliographies were performed. Additional studies known to the authors were also identified. Randomized controlled trials, reviews, and guidelines evaluating the impact of age on overall survival and/or toxicity with adjuvant and palliative therapies for colorectal adenocarcinoma were selected. A preset study selection form was applied to all identified studies. All selected studies underwent a preset study appraisal. Analyses of the effect of age on overall survival benefits and/or toxicity of therapy were extracted. A qualitative synthesis and narrative review was undertaken. There is good evidence to support that patients = 80 years of age have similar overall survival benefits with adjuvant 5-fluorouracil (5-FU)-based chemotherapy for colon cancer and with palliative first-line monotherapy for metastatic colorectal cancer, as do younger patients. Data are limited with regard to toxicity of therapy in older patients in these settings. An increase in toxicity with bolus 5-FU chemotherapy regimens is evident. There is a paucity of data regarding adjuvant treatment of older patients with rectal cancer. More elderly patients need to be enrolled in clinical trials in order to fully evaluate the outcomes of colorectal cancer therapy in this population. Further studies are warranted.

Ageism in rectal carcinoma? Treatment and outcome variations.

BACKGROUND: Rectal cancer adjuvant and neo-adjuvant therapies are associated with improved survival and local control rates. Concerns regarding adverse treatment effects tend to reduce administration in the elderly-the very population this disease affects. PURPOSE: To determine the extent to which age alters rectal cancer treatment and its outcome. METHODS AND MATERIALS: Using the population based provincial cancer registry, patients with adenocarcinoma of the rectum diagnosed between 1991 and 1998 were identified. From this cohort, a random subsample of patients seen at the regional cancer center were selected for detailed analysis. Demographic and clinical data between the provincial cohort and the subsample were compared for homogeneity. Log rank tests and Kaplan-Meier survival estimates were carried out on the subsample. RESULTS: The population cohort (n = 1979) and the subsample (n = 259) were similar in age, sex, and treatment distributions. Elderly patients (>/=75 yr) made up 23% of the rectal cancer population in Alberta. Age had a highly significant (p = 0.001) impact on whether patients received surgery alone or had surgery plus chemoradiotherapy. This corresponded to a considerable survival advantage for those elderly patients who did receive multimodality therapy (p = 0.008). CONCLUSION: The advantage of multimodality therapy in rectal cancer is confirmed in this populationbased study. Although a significant number of elderly patients are fit enough to tolerate major surgery they are being denied adjuvant therapies, presumably on the basis of potentially high treatment-related complication rates, with a subsequent reduction in survival. Strategies must be developed to ensure that maximum treatment benefit is obtained without increased harm in the elderly rectal cancer patient.

Feasibility and efficacy of a 12-week supervised exercise intervention for colorectal cancer survivors.

Exercise training improves health-related physical fitness and patient-reported outcomes in cancer survivors, but few interventions have targeted colorectal cancer (CRC) survivors. This investigation aimed to determine the feasibility and efficacy of a 12-week supervised exercise training program for CRC survivors. Feasibility was assessed by tracking participant recruitment, loss to follow-up, assessment completion rates, participant evaluation, and adherence to the intervention. Efficacy was determined by changes in health-related physical fitness. Over a 1-year period, 72 of 351 (21%) CRC survivors screened were eligible for the study and 29 of the 72 (40%) were enrolled. Two participants were lost to follow-up (7%) and the completion rate for all study assessments was ≥93%. Mean adherence to the exercise intervention was 91% (standard deviation = ±18%), with a median of 98%. Participants rated the intervention positively (all items ≥ 6.6/7) and burden of testing low (all tests ≤ 2.4/7). Compared with baseline, CRC survivors showed improvements in peak oxygen uptake (mean change (MC) = +0.24 L·min(-1), p < 0.001), upper (MC = +7.0 kg, p < 0.001) and lower (MC = +26.5 kg, p < 0.001) body strength, waist circumference (MC = -2.1 cm, p = 0.005), sum of skinfolds (MC = -7.9 mm, p = 0.006), and trunk forward flexion (MC = +2.5 cm, p = 0.019). Exercise training was found to be feasible and improved many aspects of health-related physical fitness in CRC survivors that may be associated with improved quality of life and survival in these individuals.

Critical appraisal of trastuzumab in treatment of advanced stomach cancer.

Advanced or metastatic gastric cancer constitutes the majority of patients in clinical practice. In North America, about 70% of cases are advanced or metastatic when diagnosed, which is higher than the 50% reported in Japan. This difference in presentation is reflected in 5-year overall survival, which is about 20% in North America and 40%-60% in Japan. Despite numerous efforts of randomized studies on advanced gastric cancer, no globally accepted standard regimen has yet been established. Systemic chemotherapy provides palliation and prolongs survival, but the prognosis remains poor. Several monotherapies and combined regimens are currently available and vary around the world. Additionally, several molecular targeting agents are under evaluation in international randomized studies. Human epidermal growth factor receptor-2 (HER-2) is overexpressed or amplified in approximately 22% of patients with gastric cancer. Trastuzumab, a recombinant humanized anti-HER-2 monoclonal antibody, is the first biological therapy that has showed a survival improvement by nearly three months (reduced risk of death by 26%). Therefore, trastuzumab in combination with cisplatin is a reasonable treatment option for patients with advanced gastric cancer who are HER-2 positive. This paper will focus on trastuzumab, its chemical and pharmacological characteristics, and the relevant efficacy, safety, and tolerability studies.

Added value of health-related quality of life measurement in cancer clinical trials: the experience of the NCIC CTG.

Health-related quality-of-life (HRQoL) data are often included in Phase III clinical trials. We evaluate and classify the value added to Phase III trials by HRQoL outcomes, through a review of the National Cancer Institute of Canada Clinical Trials Group clinical trials experience within various cancer patient populations. HRQoL may add value in a variety of ways, including the provision of data that may contrast with or may support the primary study outcome; or that assess a unique perspective or subgroup, not addressed by the primary outcome. Thus, HRQoL data may change the study's interpretation. Even in situations where HRQoL measurement does not alter the clinical interpretation of a trial, important methodologic advances can be made. A classification of the added value of HRQoL information is provided, which may assist in choosing trials for which measurement of HRQoL outcomes will be beneficial.

Cisplatin overdose: toxicities and management.

Cisplatin is one of the most widely used antineoplastic agents in the treatment of solid tumour and haematological malignancies, including cancers of the testes, ovary, bladder, head and neck, oesophagus, stomach and lung, as well as lymphoma and osteosarcoma. Its non-specific targeting commonly results in adverse effects and toxicities affecting the gastrointestinal, renal, neurological and haematological systems even when administered at standard doses. Since cisplatin-related toxicities are dose-dependent, these may be more pronounced in the setting of a cisplatin overdose, resulting in significant morbidity and/or mortality. The incidence of cisplatin overdoses is unknown; however, early-phase clinical trials utilizing high-dose cisplatin, and case reports in the overdose setting have characterized the clinical features associated with cisplatin overdoses, highlighting some therapeutic strategies for consideration. To date, no published guidelines exist for managing a cisplatin overdose. The major toxicities of a cisplatin overdose include nausea and vomiting, renal insufficiency, electrolyte abnormalities, myelosuppression, ototoxicity, peripheral neuropathy, hepatotoxicity and retinopathy. Diarrhoea, pancreatitis, seizures and respiratory failure have also been reported. No specific antidote for cisplatin exists. Key management principles and strategies to lessen toxicities include renoprotection and enhancing drug elimination with aggressive intravenous hydration with or without the use of an osmotic diuretic, and avoidance of nephrotoxic medications. Sodium thiosulfate and plasmapheresis, with or without haemodialysis support, should be strongly considered. Close monitoring of clinical and laboratory parameters, and institution of supportive therapies, including antiemetics and haematopoietic colony stimulating factor support, are warranted. Based on the current literature, experimental therapies such as amifostine, ditiocarb sodium (diethyldithiocarbamate), acetylcysteine, fosfomycin and colestipol are of limited clinical effectiveness and remain investigational. This review serves to highlight the clinical spectrum of toxicities resulting from a cisplatin overdose, to critically appraise the available literature and to present a suggested algorithmic approach for the initial management of a cisplatin overdose.

Trastuzumab for gastric cancer.

BACKGROUND: Gastric cancer is a disease with different management approaches in different regions, especially between Western and Asian countries. Surgery is the mainstay of treatment for non-metastatic disease. Perioperative chemotherapy or adjuvant radio-chemotherapy is recommended, since recurrences are common after curative resection. Unfortunately, advanced or metastatic gastric cancer constitutes the majority of patients in clinical practice. For these patients systemic chemotherapy is the standard treatment, to provide palliation and prolong survival; however, prognosis remains poor. Several molecular targeting agents are under evaluation in international randomized studies. OBJECTIVE: To review chemotherapy and targeted therapies for gastric cancer, chemical and pharmacological characteristics of trastuzumab, and evidence for its clinical use in gastric cancer. METHODS: Examination of relevant literature. RESULTS/CONCLUSIONS: HER-2 is overexpressed/amplified in approximately 22% of gastric cancer patients. Trastuzumab, a recombinant humanized anti-HER-2 monoclonal antibody, is, to our knowledge, the first biological therapy that has showed a survival improvement by nearly 3 months (reduced risk of death by 26%), thus trastuzumab in combination with chemotherapy is a treatment option for patients with HER2-positive advanced gastric cancer. Trastuzumab's role in curative gastric cancer treatment needs to be studied, as well as monotherapy, maintenance therapy and second line treatment in the palliative setting.